Optimizing Care for Patients With Schizophrenia

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Optimizing Care for

Patients With Schizophrenia

(page 217 in syllabus)

Andrew J. Cutler, MD

Courtesy Assistant Professor, Department of Psychiatry

University of Florida

CEO and Medical Director, Florida Clinical Research Center, LLC

Sponsored by the Neuroscience Education Institute

Additionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported by an educational grant from Lilly USA, LLC.

For further information concerning Lilly grant funding visit, www.lillygrantoffice.com.


Faculty Editor / Presenter

Andrew J. Cutler, MD, is a courtesy assistant professor in the department of psychiatry

at the University of Florida in Gainesville, and the CEO and chief medical officer of

Florida Clinical Research Center, LLC in Maitland.

Grant/Research: Alkermes, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,

Dainippon Sumitomo, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lilly,

Lundbeck, Merck, Ortho-McNeil, Otsuka America, Quintiles Transnational, Roche,

Shionogi, Shire, Sunovion, Supernus, Takeda, Targacept

Consultant/Advisor: AstraZeneca, Bristol-Myers Squibb, Cypress, Dainippon Sumitomo,

Forest, Janssen, Labopharm, Lilly, Merck, Ortho-McNeil, Otsuka America, Pamlab,

PharmaNeuroBoost N.V., Quintiles Transnational, Shionogi, Shire, Sunovion, Supernus,

Takeda, Targacept

Speakers Bureau: AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo, Forest,

GlaxoSmithKline, Janssen, Labopharm, Lilly, Merck, Ortho-McNeil, Otsuka America,

Pamlab, Shionogi, Shire, Sunovion

Individual Disclosure Statement


Learning Objectives

• Implement evidence-based treatment strategies

that are aligned with recovery goals set by the

patient

• Integrate novel treatment approaches into

clinical practice according to best practices

guidelines

• Include strategies for monitoring and addressing

adherence as part of the treatment plan for all

patients



Pretest Question 1

Theresa is a 49-year-old patient with schizophrenia

and a history of nonadherence. She does not want to

try a depot formulation due to a fear of needles. Given

that complexity of dosage regimen may adversely

affect treatment adherence, which atypical

antipsychotic would you consider for Theresa?

1. Asenapine

2. Iloperidone

3. Quetiapine XR

4. Ziprasidone


Pretest Question 2

Joel is a 23-year-old patient with schizoaffective

disorder. He is currently taking a relatively low dose of

clozapine but is considering stopping his medication

due to side effects, especially daytime sedation. Based

on receptor binding profiles, which antipsychotic has

the least risk of causing sedation?

1. Aripiprazole

2. Olanzapine

3. Quetiapine

4. Asenapine


Pretest Question 3

Henry is a 34-year-old patient with schizophrenia.

Results from the Positive and Negative Syndrome

Scale (PANSS) reveal numerous symptoms, especially

in the General Psychopathology subscale. Imaging of

Henry’s brain would likely reveal loss of gray matter in

which brain region?

1. Temporal lobe

2. Frontal lobe

3. Anterior cingulate gyrus


What Should Ideal Care Provide for

Patients With Schizophrenia?


Recovery

• Recovery from illness

– Cure of illness, absence of illness

vs

• Recovery in illness: being in recovery

– Process of managing illness more effectively

– Having a meaningful life in the community

– Moving ahead with one’s life despite illness

Davidson L et al. Schizophr Bull 2008;34:5-8.


Symptom management

Physical health

Reduced hospitalization

Reduced criminal activity

Reduced substance abuse

Stable housing

Employment

Treatment alliance

Cognitive ability

Empowerment

Community involvement

Family involvement

RECOVERY


Schizophrenia PORT

• Patient Outcomes Research Team

• Makes conservative recommendations based

solely on substantial scientific evidence

– From systematic literature reviews

• Includes psychopharmacological and

psychosocial treatment recommendations

Kreyenbuhl et al. Schizophr Bull 2010;36(1):94-103.


2009 Updated PORT Psychopharmacological

Treatment Recommendations • First and Foremost

– Conventional or atypical antipsychotics as first-line treatments • Clozapine and olanzapine should not be used first line

• More Is More – Higher doses of antipsychotics for patients with multiple episodes

• Don’t Stop – Continuous antipsychotic maintenance treatment

• Not Just a Pain in the… – Long-acting injectable formulations

• Shake It Up • Antiparkinson medications to prevent EPS

• Be Cloz-Minded – Clozapine for treatment-resistant cases

• Chillax! – Benzodiazepines for acute agitation

• Quitters Win – Smoking cessation assistance

• A Little Shocking – Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant

auditory hallucinations

Buchanan et al. Schizophr Bull 2010;36(1):71-93.


2009 Updated PORT Psychosocial Treatment

Recommendations

• Get Your ACT Together – Assertive Community Treatment

• Hi-Ho, Hi-Ho, It’s Off To Work We Go – Supported employment

• Out of the Frying Pan and Into the Skill-et – Skills training

• Think About It – Cognitive psychotherapy

• You Can Do It! – Positive reinforcement

• It’s a Family Affair – Family intervention

• Drugs Are Bad, Mmkay? – Substance abuse treatment

• Be a Loser – Weight management

Dixon et al. Schizophr Bull 2010;36(1):48-70.


Symptom Management


Early Risperidone Responders Show Early and

Consistent Improvement: Clinical Outcomes

Kinon B et al. Schizophr Res 2010;118:176-82.

0 2 4 6 8 10 12 14

0

-5

-10

-15

-20

-25

-30

-35

-40

Weeks

Least

Sq

uare

s M

ean

Ch

an

ge in

PA

NS

S T

ota

l S

co

re

* * * * * *

Early Responders (ER) (n = 144)

Early Non-Responders (ENR) (n = 192)

*P < 0.001


Early Risperidone Responders Show Early and

Consistent Improvement: Functional Outcomes

Kinon B et al. Schizophr Res 2010;118:176-82.

SOFI: Schizophrenia Objective Functioning Instrument

Overall Living

Situation

Instrumental

Activity

Productive

Activity

Social

Functioning

Le

ast

Sq

uare

s M

ean

Ch

an

ge in

SO

FI

Baseli

ne t

o E

nd

po

int

*P < 0.001

0

-2

-4

6

4

2

12

10

8

16

14

ER Group

ENR Group *

*

* * *


Duration and Severity of Untreated Psychosis

and Outcome in First-Episode Schizophrenia

• Meta-analysis of 43 publications

• Prolonged duration of untreated psychosis prior to the initiation

of treatment was associated with poorer symptomatic and

functional recovery in initial episodes

Perkins DO et al. Am J Psychiatry 2005;162(10):1785-1804.

Effect Size (95% CI)

-0.2 0.0 0.2 0.4

Global Psychopathology

Positive Symptom Severity

Negative Symptom Severity

Global Functional Outcome


FIN-11 Study

Tiihonen et al. Lancet 2009;374(9690):620-7.

Risk of death from any cause vs cumulative use of any antipsychotic drug

*Mortality = unadjusted absolute risk per 1000 person-years

†No antipsychotic drug = patients (18,914) who had not used any antipsychotic drugs during follow-up

• Long-term antipsychotic use associated with

lower mortality compared to no antipsychotic use

in patients with schizophrenia

Favors antipsychotic Favors no antipsychotic


Efficacy of Antipsychotics on Positive and

Negative Symptoms of Schizophrenia

Potkin SG et al. Int J Neuropsychopharmacol 2009;12:1233-48.


Efficacy of Antipsychotics on Symptoms of

Schizophrenia

Guo X et al. Psychopharmacology 2011; Epub ahead of print.


Efficacy of Antipsychotics on Negative

Symptoms of Schizophrenia

Stahl S et al. J Clin Psychopharmacol 2010;30:425-30.

* P < 0.05 vs HAL; ** P < 0.01 vs HAL

n = 227 n = 221 n = 151


Efficacy of Antipsychotics on Cognitive

Symptoms of Schizophrenia

Harvey PD et al. J Neuropsychiatry Clin Neurosci 2006;18:54-63.


Antipsychotics Can Improve Illness Insight

Guo X et al. Psychopharmacology 2011; Epub ahead of print.


The Bottom Line

For many patients

• Antipsychotic treatments may ameliorate

symptoms of schizophrenia if they are

maintained for an extended period of time

• Continuous maintenance antipsychotic

medication results in ~70% reduction in risk of

relapse

Lindenmayer et al. J Clin Psychiatry 2009;70(7):990-6;

Marder. J Clin Psychiatry 2003;64(Suppl):3-9.


Treatment Adherence

Antipsychotics Don’t Work At All

If They Aren’t Taken


How Common Is Nonadherence?

• Nonadherence is estimated to be as high as 60%

• 40% of annual costs for rehospitalization are due to

nonadherence

• 75% of patients who discontinue their medication

experience significant symptom exacerbation over 1

year compared to 25% of those who adhere to their

medication

• Treatment nonadherence is associated with up to a

7-fold increased risk of suicide attempt

Lindenmayer et al. J Clin Psychiatry 2009;70(7):990-6;

Marder. J Clin Psychiatry 2003;64(Suppl):3-9.


Assessing Nonadherence

•Unreliable

Patient self-report

•Overly optimistic

Physician report

•Easily manipulated

Pill counts

•Medication must be obtained from a single source

Rx renewals

•Expensive

Microelectric monitoring of pill caps

• Invasive

Physiological monitoring

Rx

llorca et al. Psychiatry Res 2008;161:235-47;

Marder. J Clin Psychiatry 2003;64(Suppl):3-9;

Velligan et al. Psychiatr Serv 2007;58(9):1187-92. .

.

Feasib

ility

Accu

rac

y

Nope, Doc,

I haven’t

missed a

single dose

She seems

like an

adherent

patient

Ouch!


Why Don’t Patients Take Their

Medicine?


Factors That May Affect

Medication Adherence

• Poor illness insight

• Cognitive deficits

• Positive symptoms

• Doctor/patient relationship

• Treatment efficacy

• Side effects

• Treatment regimen

• Drug abuse

Lieberman et al. N Engl J Med 2005;353(12):1209-23;

Piette et al. Arch Intern Med 2005;165(15):1749-55; Novick et al. Psychiatry Res 2010;176:109-13.


Relationship Between Symptoms and

Adherence


Consequences of Nonadherence


Progressive Gray Matter Loss in Adolescent Patients With Schizophrenia Over 5 Years

Thompson PM et al. PNAS 2001;98(20):11650-5.

Normal Subjects

Subjects With Schizophrenia

Difference

0.00002

0.0001

0.0005 0.001

0.005 0.01 0.05

P-Value


-5.05

-6.52

-6.00

Talairach coordinate (axial): z=3

Baseline

Gray Matter Loss in Adult Patients With

Schizophrenia at Baseline and 5-Year Follow-Up

van Haren NE et al. Neuropsychopharmacology 2007;32(10):2057-66.

-5.05

-7.60

-6.00

-7.00

5-year Follow-Up

Talairach coordinate (axial): z=3

Excessive gray matter loss was related to an increased number of hospitalizations (increased psychotic episodes)


Psychosis and Brain Volume Changes During

the First 5 Years of Schizophrenia

Gray Matter Lateral Ventricle Volume 3rd Ventricle Volume

Duration of Psychosis (months) Duration of Psychosis (months) Duration of Psychosis (months)

Cahn W et al. Eur Neuropsychopharm 2009;19:147-51.

N = 48


Reduced Gray Matter Volume in Antipsychotic-Naïve

Patients With First-Episode Schizophrenia Correlates With

Functional Deficits

Lui S et al. Am J Psychiatry 2009;166:196-205.

Temporal Lobe Abnormalities Anterior Cingulate Gyrus Abnormalities

Correlate with:

Global Assessment of Functioning (GAF) Scale

PANSS Positive Symptoms

PANSS General Psychopathology

PANSS Thought Disturbance

PANSS Activation

PANSS Paranoia

PANSS Impulsive Aggression

Correlate with:

Global Assessment of Functioning (GAF) Scale

PANSS Positive Symptoms

PANSS Thought Disturbance

PANSS Activation

PANSS Paranoia

PANSS Impulsive Aggression


Gray Matter Loss Is Worse in Patients With a

Longer Duration of Untreated Psychosis

Colored voxels depict brain areas of significantly greater gray matter loss in

patients with a long duration of untreated psychosis (>18 wks) compared to those

with a short duration (<18 wks)

Malla AK et al. Schizophr Res 2011;125(1):13-20.

http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6TC2-51DG6S4-1&_image=B6TC2-51DG6S4-1-4&_ba=&_rdoc=1&_fmt=full&_orig=na&_issn=09209964&_pii=S0920996410015501&view=full&_isHiQual=Y&_acct=C000059602&_version=1&_urlVersion=0&_userid=4429&md5=a0f38c69f5d16ba00067d04525f4e3b3


Antipsychotic Treatment Improves Cerebral Functioning

Lui S et al. Arch Gen Psychiatry 2010;67(8):783-92.

Baseline untreated patients with first-episode

schizophrenia have decreased amplitude of

low-frequency fluctuations

Patients treated for 6 wks with antipsychotics

have increased amplitude of low-frequency

fluctuations compared to baseline

Patients treated for 6 wks with

antipsychotics have increased

amplitude of low-frequency

fluctuations compared to controls


Consequences of Nonadherence on

Functional Outcomes

• Nonadherence is associated with:

– Alcohol-related problems

– Reduced mental functioning

– Reduced satisfaction with life

– Psychiatric hospitalizations

– Use of emergency psychiatric services

– Arrests

– Violence

– Victimizations

– Substance use

Ascher-Svanum et al. J Clin Psychiatry 2006;67(3):453-60.


Nonadherence Is Associated With Increased

Hospitalization

Weiden et al. Psychiatr Serv 2004;55:886-91.

0

5

10

15

20

25

0 1-10 11-30 >30 Total

% o

f P

ati

en

ts H

osp

itali

zed

Maximum Gap in Therapy (days within one year)


Partial Nonadherence

• Patient reduces dose of drug or fails to take

drug from time to time

• Can lead to unexplained and unanticipated

adverse events

• Suboptimal treatment increases risk of relapse

– A 20% reduction in treatment compliance predicts a

3.1 point increase in PANSS total score

Perkins et al. J Clin Psychiatry 2008;69(1):106-13;

Docherty et al. American College of Neuropsychology 41st Annual Meeting. Abstract 2002:154.


Even Partial Nonadherence Is Detrimental

• Nonadherent patients defined here are those who miss <50% of

their medication for 2 weeks or more

• Missing even <25% of medication for >2 weeks increases the risk

for psychotic relapse

Subotnik KL et al. Am J Psychiatry 2011;168:286-92.

http://ajp.psychiatryonline.org/content/vol168/issue3/images/large/appi.ajp.2011.168.3.286.jpeg


Improving Treatment Adherence


How to Improve Adherence

• Minimize side effects and increase drug efficacy

– By switching to another antipsychotic

• Utilize long-term depot formulations

• Psychosocial interventions

• Maximize cognitive functioning


Strategies to Improve Adherence

• Basic communication

– Take the patient's preferences into account

– Explain the benefits and hazards of treatment options

• Strategy-specific interventions

– Adjusting medication timing and dosage for least intrusion

– Minimize adverse effects and maximize effectiveness

• Reminders (psychosocial interventions)

• Evaluate adherence regularly

Mitchell, Selmes. Adv Psychiatr Treatment 2007;13:336-46.


Maximize Treatment Efficacy While Minimizing

Side Effects for the Individual Patient


Long-Acting Depot Formulations


Long-Acting Injectable (LAI) Antipsychotics to

Improve Medication Adherence

• Cost/insurance coverage

• More appointments

• Oral to LAI conversion

• Perceived stigma

• Negative perceptions by clinicians

• Assured medication delivery

• Continuous antipsychotic coverage

• No need to remember to take medication every

day

• Drug remains in system for 1-2 weeks after a

missed dose

• Reduced risk of relapse and rehospitalization

• Avoidance of first-pass metabolism

• Peak plasma level is lower and occurs less

often (less side effects?)

• More frequent contact with treatment team

• Increasing number of options available

Advantages Disadvantages

Gerlach. Int Clin Psychopharmacol 1995;9(5):17-20.


Atypical Antipsychotics With Long-Acting

Depot Formulations

aripiprazole 4 wk in trials

iloperidone 4 wk in trials

olanzapine 2 wk

4 wk

risperidone 2 wk

4 wk in trials paliperidone

4 wk

12 wk in trials


Depot Injections Are Associated With a 50-65% Lower Risk of Rehospitalization Compared to Their

Oral Counterparts

Tiihonen J et al. Am J Psychiatry 2011;168:603-9.

http://ajp.psychiatryonline.org/content/vol168/issue6/images/large/appi.ajp.2011.603a.jpeg


Not All Studies Show Superiority of Depot

Antipsychotics

Rosenheck RA et al. N Engl J Med 2011;364:842-51.


Characteristics That May Affect Adherence

Morrissette D, Stahl S. Neuroscience Education Institute. http://www.neiglobal.com. Accessed Sept 2010.


Psychosocial Intervention


Psychosocial Interventions

• Supported employment

• Cognitive behavioral therapy (CBT)

• Cognitive adaptation therapy (CAT)

• Cognitive remediation therapy (CRT)


Pharmacy-Based Intervention

Valenstein et al. Schizophr Bull 2009; Epub ahead of print.


Cognitive Remediation Therapy

McGurk et al. Am J Psychiatry 2007;164:1791-1802.

0

0.1

0.2

0.3

0.4

0.5

0.6

Eff

ect

Siz

e


ACT Now!

Recovery Is Going Fast!


Elements of ACT

• Developed in the 1970s

• Goal

– Replace crisis-oriented clinical care with intensive

community-based intervention

• Design

– Integrative care is continuous and offered for as

long as it is needed

– Care is available 24/7

– Team approach to care

Dixon L. Psychiatr Serv 2000;51(6):759-65.


The ACT Team

ACT leader

Psychiatrists

Psychiatric nurses

Employment specialist

Substance abuse specialist

Peer specialist

Additional mental health professionals

Program assistant

• The team meets regularly to discuss each case

• At least one team member visits the patient on a regular basis to assess medication efficacy, treatment adherence, medication side effects, physical health, and other issues that could potentially affect recovery

Dixon L. Psychiatr Serv 2000;51(6):759-65.


Symptom management

Physical health

Reduced hospitalization

Reduced criminal activity

Reduced substance abuse

Stable housing

Employment

Treatment alliance

Cognitive ability

Empowerment

Community involvement

Family involvement

RECOVERY

ACT Services Element of Recovery

•Medication prescription, administration, and monitoring •Illness management and recovery skills •Continuous assessment and intervention

•Medication prescription, administration, and monitoring •Continuous assessment and intervention •Medical care

•Crisis assessment and intervention •Illness management and recovery skills •Medication prescription, administration, and monitoring •Illness management and recovery skills •Medication prescription, administration, and monitoring •Individual supportive therapy

•Substance abuse treatment •Illness management and recovery skills •Individual supportive therapy

•Housing support services

•Employment-support services

•Transportation

•Intervention with support networks

•Transportation

•Intervention with support networks

•Individual supportive therapy

•Frequent interaction with ACT team members

•Integration of patient’s wishes in treatment planning

•Individual supportive therapy •Assistance with activities of daily living •Case management

•Integration of patient’s wishes in treatment planning

•Incorporation of recovering patients as peer specialists on ACT team


Is ACT Worth It?

• Direct and indirect costs of treating schizophrenia are ~$60 billion

– 2/3 of these costs are from hospitalizations

• Increased cost of ACT-based care is offset by:

– Reduced hospitalizations

– Reduced use of emergency services

– Reduced criminal activities and justice system use

– Increased engagement in the workforce

– Decreased use of welfare services

– Reduced death from suicide

• May be most cost-effective for patients who are severely disabled by their illness, have numerous hospitalizations, or are at high risk for relapse

Rosen A et al. J Rehab Res Dev 2007;44(6):813-26; Gilmer TP et al. 2010;67(6):645-52;

McCrone P et al. Br J Psychiatr 2010;196:377-82.


Summary

• Symptom management is just a portion of what is necessary for optimizing outcomes for patients with schizophrenia

• Antipsychotic treatments ameliorate symptoms of schizophrenia for many patients and should be initiated early in the disease course

• Treatment nonadherence greatly increases the risk of poor functional outcomes in schizophrenia; even partial nonadherence increases the risk for relapse

• Minimization of treatment side effects may help to maximize treatment adherence; establishing a strong treatment alliance and optimizing treatment for the individual patient can increase adherence

• Long-acting depot formulations of antipsychotics offer the benefit of better ensuring treatment adherence

• Psychosocial interventions and the mediation of cognitive deficits should also be integral parts of treatment for schizophrenia

Documents

Optimizing Care for Patients With Schizophrenia